MANAGEMENT OF HBV & HCV INFECTION...

MANAGEMENT OF HBV & HCV

INFECTION---SIMILARITIES &

DISSIMILARITIES---PAST AND

PRESENT

Professor Salimur Rahman Department of Hepatology, BSMMU

President, Association for the study of the liver, Dhaka,

Bangladesh

President, South Asian Association for Study of the Liver

Chairman, Viral Hepatology Foundation Bangladesh

Executive Committee Member, APASL

HAV, HEV HBV, HCV, HDV

HGV, TTV

HEPATOTROPIC VIRUSES

1. HBV infection

a. Diagnosis

b. Treatment

I) Past

II) Present

2. HCV infection

a. Diagnosis

b. Treatment

I) Past

II) Present

Both HBV and HCV causes acute and chronic

hepatitis

Acute hepatitis due to HBV approximately 22%

and due to HCV approximately 3%.

Chronic hepatitis due to HBV approximately 80 %

and due to HCV approximately 4%.

Hepatitis B

only 5 % develop chronicity in adult

Hepatitis C

75% - 85 % develop chronicity .

Acute liver failure

Cholestatic hepatitis

Aplastic anaemia

Chronic liver disease and

Cirrhosis

Relapsing hepatitis

HBV is a member of the

hepadnaviridae

(hepatotrophic DNA)

family

Main routes of

transmission of HBV are

parenteral, sexual and

perinatal

7

In 1965, Dr. Baruch S. Blumberg discovered the virus.

Named “Australia antigen” Received the Nobel Prize in

Medicine in 1976

Australia antigen is now called hepatitis B surface antigen (HBsAg).

8

• CHB is a healthcare concern globally, particularly in Asia • More than 400 million people are chronic carriers • 15–40% of these will develop serious outcomes, such as cirrhosis, liver failure and hepatocellular carcinoma • Disease from chronic infection accounts for >1 million deaths/year (10th leading cause of death worldwide) • Liver cancer is the sixth most common cancer worldwide

10

5.4 % healthy individuals.

7.5% healthy job seekers.

19-29% professional blood donors.

5.4% in slum population (BMRC).

CLD: 40% and HCC: 47%- due to HBV.

11

Acute HBV infection

12

>90% of children

<5% of adults

Recovery

protective immunity

Transplant or death

Chronic HBV infection

Hepatocellular

carcinoma (HCC) Cirrhosis

30–40% risk

McMahon BJ. Semin Liver Dis. 2005;25(Suppl 1):3-8.

13

HBV ACUTE /CHRONIC HEPATITIS B

CIRRHOSIS ESLD

HEPATOCELLULAR CARCINOMA

Cirrhosis HCC Normal Cirrhosis

Liver disease progression over time

Liver damage = the result of attempts, usually unsuccessful, to clear infected hepatocytes as part of the immunoclearance stage of disease

14

< < > > HBeAg-positive HBeAg-negative

ALT

HBV-DNA

Normal/

mild CHB

Moderate/severe CHB Moderate/severe CHB Normal/mild

CHB Cirrhosis

Inactive-carrier

state

HBeAg-negative

CHB

HBeAg-positive

CHB

Immuno- tolerant

phase Low replicative phase

Reactivation phase

Cirrhosis Inactive cirrhosis

Immune clearance

phase

Course of CHB Infection

Precore mutant

In this ‘‘HBsAg-negative phase” after

HBsAg loss, low-level HBV replication

may persist with detectable HBV DNA in

the blood (Occult HBV).

15

Rest

Dietary advice

Symptomatic management

Management of complications

S. bilirubin more than 10 mg/dl.

Prothombin time: INR more than 1.5.

Presence of Ascites.

Associated with any malignancy.

Plan for chemotherapy

Clear the virus

Suppress the virus

Reduce liver injury

Prevent fibrosis

18

HBV

Prevention of cirrhosis, and HCC

Decision to treat

19

IFN

(Peg IFN alfa-2a)

Nucleos(t)ide

analogues

20

Direct antivirals Interferon-based

Patient/physician preference

Consider risk of drug resistance

Length of treatment

Side effects

Immunocompet

ent

Compensated

liver

disease

Younger

patients

NA-

failures/resista

nt

Who should be treated with what?

Immunosuppressed

Advanced liver

disease

IFN/PEG-IFN

non-responders

High ALT

Low HBV DNA

Liver lesions

All HBV carriers are potential treatment

candidates; it is only a matter of time

before they reach the criteria generally set

for initiation of treatment

Which Patients Should Be Treated?

ALT levels

HBeAg status

HBV DNA levels

Histological grade and stage

Cirrhosis vs no cirrhosis

Compensated vs decompensated disease

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Chronic necroinflammatory disease of the liver caused by

persistent infection with hepatitis B virus >6 months.

23

Diagnostic Criteria of CHB

1. HBsAg +ve >6 months

2. Serum HBV DNA >20,000 IU/ml (105copies/ml) in HBeAg +ve ,

> 2,000 IU/ml (104copies/ml) in HBeAg - ve CHB

3. Persistent or intermittent elevation in ALT/AST levels

4. Liver biopsy showing chronic hepatitis with moderate or severe necro

inflammation

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1992 1998 2002 2005 2006 2008 and

beyond…

IFN alfa LAM

ADV ETV

PegIFN alfa-2a

LdT Tenofovir

Clevudine

Combination Rx?

“The New Era”

Oral therapy

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No treatment

Monitor every 6–12 months Monitor every 3–12

months (immune tolerant)

Consider biopsy, if age >35–40 years; treat if significant disease

Liver biopsy optional

Treat

HBeAg positive

ALT elevated

>2 times

normal

ALT normal/<2

times normal

HBV DNA

≥105 copies/mL

HBV DNA

<105 copies/mL

ALT normal

26

No treatment

Monitor every 6–12 months

Monitor ALT, or

Consider biopsy, since ALT often fluctuates; treat if significant disease

Long-term treatment required

Treat

Liver biopsy optional

Long-term treatment required

HBeAg negative

ALT elevated

(>2 times)

ALT normal/

<2 times

HBV DNA

≥104 copies/mL

HBV DNA

<104 copies/mL

ALT normal

27

May choose to treat or observe

Treat

HBV DNA

(PCR) HBV DNA

<104 copies/mL

HBV DNA

≥104 copies/mL

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936.

Courtesy of Emmet Keeffe, MD.

Detectable DNA require urgent antiviral treatment with

NA(s).

Significant improvement associated with control of viral

replication

Antiviral therapy not sufficient to rescue some patients

with very advanced liver disease and considered for

liver transplantation

PEG- IFN is contraindicated during pregnancy .

Lamivudine, adefovir and entecavir are listed by the FDA as

category C drugs.

Telbivudine and tenofovir as category B drugs.

*HBV DNA <10,000 copies/mL

and ALT normal

6 months post-treatment

Sustained response*

HBV DNA decline (copies/mL)

ANY HBsAg decline

WEEK 12 102

HBeAg-patients

No

N=54

<2 log N=20

0/20 (0%)

≥2 log N=34

8/34 (24%)

Yes

N=48

<2 log N=20

5/20 (25%)

≥2 log N=28

11/28 (39%)

Analysis of 102 patients with available HBV DNA and HBsAg levels (80% genotype D)

Rijckborst et al. Hepatology 2010

e-

New milestones are needed to cure HBV

infection with agents which

Act on all possible sites of viral replication

cycle – from entry into hepatocytes to

release into circulation

Act on host immune system to clear up virus

Immune modulator is one of the options

N=

18

No

. o

f p

ati

en

ts

Before

vaccination

18

12

6

After 5 nasal

vaccination

After 10

vaccinations

12 months

after end of

vaccinations

N=

5

N=

6

N=

9

Antiviral effect of HBsAg/HBcAg vaccine in

CHB patients HBV DNA positive in the sera

HBV DNA undetectable (<500 copies/ml) in the sera

Hepatitis B virus is a common problem for

Bangladesh as well as globally

Concept of management of hepatitis B is

continuously changing and improving

Peginterferon is one of the best treatment

option, because of definite duration, no

resistance, durable off treatment response

Newer NUCs of high genetic barrier are next

possible approach

Immune modulator is one of the future

options

33

4 times more prevalent than AIDS worldwide

Increases the risk for HCC by 25 fold

Causes 3-4 times more liver related death than HBV

No vaccine available to prevent Hepatitis-C

HCV the silent killer

Identified and genome cloned in 1989

Family : Flaviviridae

Genus : Hepaciviruses

Spherical, enveloped, single-stranded

RNA virus

Replication - > 1 trillion per day

HCV

Source WHO 1999

170-200 million Carriers Worldwide

3-4M

30-35M

60M

3-4M

12-15M

10M

3-4M

5M

Total area: 1,47570sq. km

Population: 158.8 mil

Population density/sq. km: 1090

World bank, 2007

HCV: Prevalence in Bangladesh 0.8%

NATURAL HISTORY OF HCV INFECTION

In acute infection :

• 20% may clear the virus

spontaneously

• Symptomatic patients are more

likely to clear

• Most patients do so within 12

weeks

• 80% of patients develop chronic

infection

Enzyme immunoassay (EIA) detects 95% of

infections

Recombinant immunoblot assay (RIBA)

Molecular tests - HCV RNA

(qualitative and quantitative)

Genotype testing

To prevent hepatic cirrhosis, decompensation of cirrhosis, HCC and death.

The endpoint of therapy is undetectable HCV RNA in a sensitive assay (<15 IU/ml) 12 and 24 weeks after the end of treatment (i.e. an SVR)

In patients with cirrhosis, HCV eradication reduces the rate of decompensation and will reduce, albeit not abolish, the risk of HCC. In these patients surveillance for HCC should be continued

Liver disease severity

Identifying patients with cirrhosis

Fibrosis stage

Presence of ascites

HCV RNA detection

The HCV genotype

IL28B genotyping

EVOLUTION OF HCV TREATMENT

Discovery of HCV genome

Addition of RBV to IFN alfa improved outcomes

Peg-IFN alfa plus RBV becomes gold standard

Treatment with IFN alfa for 24 or 48 weeks – 3x

weekly dosing – Poor outcomes

Development of Peg-IFN – once-weekly dosing – Outcomes

improved further

1989 2007

New antivirals enter development

Response-guided therapy emerging

Pegylated IFN-α2a - 180 μg/week

Pegylated IFN-α2b - 1.5 μg/kg/week

Ribavirin - 1000 or 1200 mg/day

based on body weight (<75 kg or ≥75 kg,

respectively)

Sofosbuvir - 400 mg (one tablet)/day

Simeprevir - 150 mg (one capsule) once per

day

Daclatasvir - 60 mg /day

(Only recommended by EASL)

Sofosbuvir is a prodrug of a nucleotide

analogue inhibitor of the HCV NS5B

RNA-dependent RNA polymerase.

Approved By FDA In DEC 2013.

• Directly acts on HCV to inhibits

HCV NS5B RNA-dependent RNA

polymerase, an enzyme essential

for viral replication and acts as a

chain terminator

Indications:

• Genotypes 14 chronic HCV

• Hepatocellular carcinoma with HCV

• HCV/HIV co-infection

Place in therapy:

• Considered first-line therapy for patients

with HCV in combination with ribavirin and

peg-interferon

Contraindications: • Pregnancy and use in male partners of pregnant

women

• All contraindications applicable to ribavirin and peg-interferon

Warnings and Precautions • Use with potent P-gp inducers( Rifampicin)

• Pregnancy when used with ribavirin or peg-interferon

• Use as monotherapy

Pregnancy:

• US FDA pregnancy Category B (single use,

not recommended)

• Category X when used in combination with

ritonavir or peg-interferon/ribavirin

Lactation:

• Excretion in breast milk is unknown; use is

not recommended

Dosing: 400mg daily with ribavirin with/without

peg-interferon alfa

Simeprevir (150 mg daily), a specific

inhibitor of the HCV NS3/4A serine

protease

Patients with Renal Impairment

Severe Renal Impairment (CrCl <30 mL/min)

or

ESRD Requiring HD or PD

Recently the treatment of HCV infection is dramatically improved .

Peoples are now using Interferon free regime in all Genotypes .

The oral DAA are now being used even in decompensated stage of the liver disease .

With the newer regime HCV infection is now claimed to be eradicated from the planet.

We hope that the cost of the recent drugs will be come down and easily available in our country .